東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Investigation of the Effects of Alte...

Mayers, Justin.

FindBook

Google Book

Amazon

博客來

Investigation of the Effects of Alterations in the Glutamate Receptor, GRIK2 on Osteosarcoma Tumourigenesis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Investigation of the Effects of Alterations in the Glutamate Receptor, GRIK2 on Osteosarcoma Tumourigenesis./
作者:	Mayers, Justin.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	205 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Contained By:	Dissertations Abstracts International81-04B.
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13427039
ISBN:	9781085762342

Investigation of the Effects of Alterations in the Glutamate Receptor, GRIK2 on Osteosarcoma Tumourigenesis.
Mayers, Justin.

Investigation of the Effects of Alterations in the Glutamate Receptor, GRIK2 on Osteosarcoma Tumourigenesis. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 205 p.

Source: Dissertations Abstracts International, Volume: 81-04, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item must not be sold to any third party vendors.

Over the past two decades, osteosarcoma survival rates have remained stagnant, and the discovery of novel molecular alterations is necessary in clinical research. Osteosarcoma tumours were analyzed for copy number alterations on a SNP array, and recurrent copy number losses were observed in 14% of samples in the 6q16.3, suggesting this region may be important in the disease. Focal deletions were adjacent to the GRIK2 gene which encodes an ionotropic glutamate receptor, and members of other glutamate receptor families have been linked to osteosarcoma through genome wide association studies. The mechanistic relationship between the receptors and the disease is unclear, although glutamate receptors are expressed in bone cells and may disrupt the bone remodelling process, which has been hypothesized to lead to tumour formation. The goal of this study was to investigate the relationship between the focal deletions and the expression, function and regulation of the GRIK2 gene in osteosarcoma.The focal deletions overlapped with non-coding regulatory elements in the 5' intergenic space of GRIK2, and a similar trend was observed in a larger dataset that acted as a validation tool. Expression levels of GRIK2 varied in tumour samples, and there was a subset of samples with high expression that included four tumours with homozygous deletions suggesting a potential link between the deletions and expression. The functional role of GRIK2 was examined in vitro by gene overexpression experiments, and an anti-tumour phenotype was observed in cells with high GRIK2 that was marked by decreased proliferation and migration, and increased incidences of apoptosis. Additionally, the effect of deletions on GRIK2 expression regulation was examined by gene editing experiments. Targeted deletion of the SETDB1 histone methyltransferase binding sequence increased GRIK2 gene and protein levels. In conjunction with higher GRIK2 expression, levels of the repressive H3K9Me3 were decreased. The focal deletions may be involved in shifting GRIK2 from a repressed to an active state, which was associated with a less aggressive phenotype. This study has also demonstrated the potential utility of regulatory elements as possible therapeutic targets as these sequences could play roles in cancer initiation and growth.

ISBN: 9781085762342Subjects--Topical Terms:

517296
Molecular biology.

Investigation of the Effects of Alterations in the Glutamate Receptor, GRIK2 on Osteosarcoma Tumourigenesis.
LDR:03499nmm a2200397 4500 001 2263334
005 20200316071947.5
008 220629s2019 ||||||||||||||||| ||eng d
020 $a 9781085762342
035 $a (MiAaPQ)AAI13427039
035 $a AAI13427039
040 $a MiAaPQ $c MiAaPQ
100 1 $a Mayers, Justin. $3 3540418
245 1 0 $a Investigation of the Effects of Alterations in the Glutamate Receptor, GRIK2 on Osteosarcoma Tumourigenesis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2019
300 $a 205 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
500 $a Advisor: Andrulis, Irene.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2019.
506 $a This item must not be sold to any third party vendors.
520 $a Over the past two decades, osteosarcoma survival rates have remained stagnant, and the discovery of novel molecular alterations is necessary in clinical research. Osteosarcoma tumours were analyzed for copy number alterations on a SNP array, and recurrent copy number losses were observed in 14% of samples in the 6q16.3, suggesting this region may be important in the disease. Focal deletions were adjacent to the GRIK2 gene which encodes an ionotropic glutamate receptor, and members of other glutamate receptor families have been linked to osteosarcoma through genome wide association studies. The mechanistic relationship between the receptors and the disease is unclear, although glutamate receptors are expressed in bone cells and may disrupt the bone remodelling process, which has been hypothesized to lead to tumour formation. The goal of this study was to investigate the relationship between the focal deletions and the expression, function and regulation of the GRIK2 gene in osteosarcoma.The focal deletions overlapped with non-coding regulatory elements in the 5' intergenic space of GRIK2, and a similar trend was observed in a larger dataset that acted as a validation tool. Expression levels of GRIK2 varied in tumour samples, and there was a subset of samples with high expression that included four tumours with homozygous deletions suggesting a potential link between the deletions and expression. The functional role of GRIK2 was examined in vitro by gene overexpression experiments, and an anti-tumour phenotype was observed in cells with high GRIK2 that was marked by decreased proliferation and migration, and increased incidences of apoptosis. Additionally, the effect of deletions on GRIK2 expression regulation was examined by gene editing experiments. Targeted deletion of the SETDB1 histone methyltransferase binding sequence increased GRIK2 gene and protein levels. In conjunction with higher GRIK2 expression, levels of the repressive H3K9Me3 were decreased. The focal deletions may be involved in shifting GRIK2 from a repressed to an active state, which was associated with a less aggressive phenotype. This study has also demonstrated the potential utility of regulatory elements as possible therapeutic targets as these sequences could play roles in cancer initiation and growth.
590 $a School code: 0779.
650 4 $a Molecular biology. $3 517296
650 4 $a Genetics. $3 530508
650 4 $a Oncology. $3 751006
650 4 $a Physiology. $3 518431
650 4 $a Medicine. $3 641104
650 4 $a Histology. $3 641250
650 4 $a Epidemiology. $3 568544
650 4 $a Public health. $3 534748
650 4 $a Health sciences. $3 3168359
650 4 $a Pathology. $3 643180
690 $a 0307
690 $a 0369
690 $a 0992
690 $a 0573
690 $a 0571
690 $a 0566
690 $a 0564
690 $a 0414
690 $a 0766
690 $a 0719
710 2 $a University of Toronto (Canada). $b Laboratory Medicine and Pathobiology. $3 3193014
773 0 $t Dissertations Abstracts International $g 81-04B.
790 $a 0779
791 $a Ph.D.
792 $a 2019
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13427039